Experimental Hypoxia - Virtual Hypoxia & Brainstem Volume

1 Bader et al. 2026 — Experimental Hypoxia to Probe Neuro-Metabolic and Vascular Dysregulation in ME/CFS

• Full Citation:: Bader V, Estermann K, Niess E, Zrzavy T, Fischmeister F, Haider T, Ludwig B, Barkhof F, Mutsaerts HJMM, Kasprian G, Niess F, Bogner W, Kollndorfer K, Haider L. Experimental hypoxia to probe neuro-metabolic and vascular dysregulation in ME/CFS: a multimodal proof-of-concept MRI study. medRxiv. 2026. (Bader et al. 2026)
• DOI:: 10.64898/2026.08.10.26359935
• Study Design:: Single-session multimodal 3T MRI (brain volumetry, arterial spin labeling, multivoxel proton MRS) under normoxia and two controlled hypoxic challenges (SpO₂ ~87±3%).
• Sample Size:: 26 ME/CFS patients, 27 age-/sex-matched healthy controls.
• Key Findings::
  • Reduced brainstem volume in patients (1.46 vs 1.55% of eTIV; p=0.013, FDR-p=0.039); deep grey matter and whole-brain parenchymal fraction did not differ.
  • Thalamic lactate-to-creatine (Lac/tCr) elevated at normoxia in patients (0.171 vs 0.135; FDR-p=0.021; ~27% higher).
  • Thalamic Lac/tCr rose under hypoxia in controls only (FDR-p=0.028) and did not rise further in patients (FDR-p=0.38) — blunted metabolic reactivity.
  • Whole-brain CBF rose under hypoxia in both groups (controls +4.8%, patients +3.7%), with greater initial inter-individual variability in patients (patient-to-control variance ratio up to 6.94; FDR-p=0.001), absent at the second challenge.
  • Exploratory: exaggerated inverse coupling between thalamic total N-acetylaspartate (tNAA/tCr) and white-matter CBF in patients.
• Conclusion:: Provides in vivo evidence of impaired neuro-metabolic and vascular adaptive capacity in ME/CFS, supporting the virtual hypoxia hypothesis and proposing candidate imaging markers for stratification.
• Limitations:: Preprint (not peer reviewed); proof-of-concept single center; moderate sample size; cohort not stratified by severity; exploratory network analysis unadjusted.
• Certainty Assessment::
  • Quality: Medium (preprint; multimodal, well-designed, but un-peer-reviewed)
  • Sample: Medium (n=53 total)
  • Replication: Not yet replicated (first experimental-hypoxia MRI study in ME/CFS)
  • Score: 0.40 (raw 0.40 × 1.00 ME/CFS weight)

2 Thapaliya et al. 2023 — Brainstem Volume Changes in ME/CFS and Long COVID

• Full Citation:: Thapaliya K, Marshall-Gradisnik S, Barth M, Eaton-Fitch N, Barnden L. Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patients. Frontiers in Neuroscience. 2023;17:1125208. (Thapaliya et al. 2023)
• DOI:: 10.3389/fnins.2023.1125208
• Study Design:: 7T T1-weighted structural MRI volumetric comparison of brainstem regions.
• Sample Size:: 10 ME/CFS (CCC or ICC), 8 long COVID (WHO Delphi), 10 healthy controls.
• Key Findings::
  • SIGNIFICANTLY LARGER volumes in ME/CFS for pons (p=0.004) and whole brainstem (p=0.01).
  • Larger volumes in long COVID for pons (p=0.003), superior cerebellar peduncle (p=0.009), and whole brainstem (p=0.005).
  • No significant difference between ME/CFS and long COVID volumes.
  • Pons and whole-brainstem volumes positively correlated with pain; midbrain negatively correlated with breathing difficulty.
• Conclusion:: Demonstrates abnormal (larger) brainstem volume in both ME/CFS and long COVID, consistent with overlapping symptoms — but in the OPPOSITE direction to the Bader 2026 reduced-brainstem finding.
• Limitations:: Very small sample (n=28); 7T high-field with different segmentation/normalization than Bader; direction inconsistency across cohorts unresolved; single center (Griffith).
• Certainty Assessment::
  • Quality: Medium (Frontiers in Neuroscience; 7T but small n)
  • Sample: Low (n=28)
  • Replication: Partially (contrasts Bader 2026 reduced brainstem)
  • Score: 0.55 (raw 0.55 × 1.00 ME/CFS weight)

3 Barnden et al. 2018 — Hyperintense Sensorimotor T1 MRI Associated with Brainstem Abnormality in CFS

• Full Citation:: Barnden LR, Shan ZY, Staines DR, Marshall-Gradisnik S, Finegan K, Ireland T, Bhuta S. Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome. NeuroImage: Clinical. 2018;20:102–109. (Barnden et al. 2018)
• DOI:: 10.1016/j.nicl.2018.07.011
• Key Findings::
  • Decreased brainstem T1wSE signal (PFWE=0.002) and increased sensorimotor white-matter T1wSE signal in CFS.
  • Brainstem and sensorimotor values negatively correlated in both CFS (R²=0.31) and controls (R²=0.34).
  • Interpreted as brainstem conduction deficit stimulating sensorimotor myelin upregulation; VBM found no regional GM/WM volume group differences.
• Conclusion:: Supports brainstem structural/functional abnormality as a core CFS feature, consistent with reduced/atrophic brainstem rather than enlargement.
• Limitations:: Signal-based inference, not direct axonal measure; causality untested; no severity stratification.
• Certainty Assessment:: 0.55 (raw 0.55 × 1.00 ME/CFS weight)

4 Zhang et al. 2020 — Brainstem Atrophy in Gulf War Illness

• Full Citation:: Zhang Y, Avery T, Vakhtin AA, Mathersul DC, Tranvinh E, Wintermark M, Massaband P, Ashford JW, Bayley PJ, Furst AJ. Brainstem atrophy in Gulf War Illness. Neurotoxicology. 2020;78:71–79. (Zhang et al. 2020)
• DOI:: 10.1016/j.neuro.2020.02.006
• Key Findings::
  • Significant subcortical atrophy in GWI with the LARGEST effect in the brainstem, then ventral diencephalon and thalamus (111 GWI vs 59 HC).
  • Smaller brainstem volume correlated with greater fatigue and depressive symptoms.
• Conclusion:: Cross-disease model for a brainstem-volume–fatigue link in the SAME direction as the Bader 2026 reduced-brainstem finding.
• Limitations:: Gulf War Illness population, not ME/CFS; cross-sectional.
• Certainty Assessment:: 0.60 raw × 0.75 general/overlap population = discounted 0.45

5 Trapp & Stys 2009 — Virtual Hypoxia and Chronic Necrosis of Demyelinated Axons

• Full Citation:: Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurology. 2009;8(3):280–291. (Trapp and Stys 2009)
• DOI:: 10.1016/S1474-4422(09)70043-2
• Key Findings::
  • Defines “virtual hypoxia”: increased energy demand of impulse conduction along demyelinated/excitable axons plus reduced axonal ATP production induces tissue hypoxia without actual hypoxemia.
  • Downstream: mitochondrial dysfunction, Na+ influx, Ca2+ overload, AMPA receptor activation.
• Conclusion:: Foundational conceptual template the Bader 2026 study applies to ME/CFS (elevated resting brain lactate despite normal arterial O2 = intrinsic bioenergetic inefficiency).
• Limitations:: Multiple sclerosis / neurobiology model, not ME/CFS; general-population relevance only.
• Certainty Assessment:: 0.70 raw × 0.75 general population = discounted 0.52

6 Mahad, Trapp & Lassmann 2015 — Pathological Mechanisms in Progressive MS

• Full Citation:: Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurology. 2015;14(2):183–193. (Mahad, Trapp, and Lassmann 2015)
• DOI:: 10.1016/S1474-4422(14)70256-X
• Key Findings::
  • Neurodegeneration driven by microglial activation, chronic oxidative injury, mitochondrial damage accumulation in axons, and iron accumulation.
  • Mitochondrial compromise coupled with increased axonal energy demand is central (the virtual-hypoxia mechanism).
• Conclusion:: Provides the mechanistic bridge from virtual hypoxia to mitochondrial respiratory chain deficiency — the bioenergetic failure pattern the ME/CFS virtual-hypoxia hypothesis invokes.
• Limitations:: Multiple sclerosis population, not ME/CFS; general-population relevance only.
• Certainty Assessment:: 0.70 raw × 0.75 general population = discounted 0.52

7 Biswal et al. 2011 — Reduced Cerebral Blood Flow in CFS by Arterial Spin Labeling

• Full Citation:: Biswal B, Kunwar P, Natelson BH. Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling. Journal of the Neurological Sciences. 2011;301(1-2):9–11. (Biswal, Kunwar, and Natelson 2011)
• DOI:: 10.1016/j.jns.2010.11.018
• Key Findings::
  • Significantly lower global absolute CBF in CFS patients (11 CFS vs 10 HC), reduced across nearly every region.
  • Effect not homogeneous — 2 of 11 patients showed CBF increases.
• Conclusion:: Baseline CFS hypoperfusion precedent relevant to the Bader 2026 preserved-reactivity / high-variability CBF finding.
• Limitations:: Small sample; cross-sectional.
• Certainty Assessment:: 0.45 (raw 0.45 × 1.00 ME/CFS weight)

8 Staud et al. 2018 — Task-Related CBF Changes in ME/CFS (ASL)

• Full Citation:: Staud R, Boissoneault J, Craggs JG, Lai S, Robinson ME. Task related cerebral blood flow changes of patients with chronic fatigue syndrome: an arterial spin labeling study. Fatigue: Biomedicine, Health and Behavior. 2018;6(2):63–79. (Staud et al. 2018)
• DOI:: 10.1080/21641846.2018.1453919
• Key Findings::
  • Global CBF similar at rest and during PASAT task in 17 ME/CFS vs 16 HC.
  • Regional CBF changes differed between groups during post-task recovery — fatigue improvement with decreased rCBF (STG, precuneus, fusiform) in ME/CFS vs increased in HC.
• Conclusion:: Normal resting/global CBF but abnormal task-related CBF dynamics in ME/CFS — supports the Bader 2026 finding that CBF reactivity (not baseline) is dysregulated.
• Limitations:: Small sample; all-female.
• Certainty Assessment:: 0.50 (raw 0.50 × 1.00 ME/CFS weight)

9 He et al. 2013 — Cerebral Vascular Control and Skeletal Muscle pH in CFS

• Full Citation:: He J, Hollingsworth KG, Newton JL, Blamire AM. Cerebral vascular control is associated with skeletal muscle pH in chronic fatigue syndrome patients both at rest and during dynamic stimulation. NeuroImage: Clinical. 2013;2:168–173. (He et al. 2013)
• DOI:: 10.1016/j.nicl.2012.12.006
• Key Findings::
  • Resting CBF inversely correlated with skeletal muscle pH (r=-0.67, p<0.01) in 17 Fukuda CFS patients.
  • Prolonged cerebral vascular constriction during Valsalva associated with higher post-exercise muscle pH (r=0.69, p<0.008).
• Conclusion:: Links cerebral vascular control (autoregulation) to systemic metabolic state — precedent for systemic-vascular-metabolic coupling relevant to virtual-hypoxia and cerebrovascular-reactivity findings.
• Limitations:: Small sample; cross-sectional.
• Certainty Assessment:: 0.50 (raw 0.50 × 1.00 ME/CFS weight)

10 Hadanny et al. 2024 — Long-Term Outcomes of HBOT in Post-COVID Condition

• Full Citation:: Hadanny A, Zilberman-Itskovich S, Catalogna M, Elman-Shina K, Lang E, Finci S, Polak N, Shorer R, Parag Y, Efrati S. Long term outcomes of hyperbaric oxygen therapy in post covid condition: longitudinal follow-up of a randomized controlled trial. Scientific Reports. 2024;14(1):3604. (Hadanny et al. 2024)
• DOI:: 10.1038/s41598-024-53091-3
• Key Findings::
  • Improvements in quality of life, sleep, psychiatric, and pain symptoms persisted ~1 year after 40 HBOT sessions in 31 post-COVID patients (sleep ES 0.47–0.79; pain severity ES 0.69; pain interference ES 0.83).
  • Prior RCT reported cognitive, fatigue, sleep, and pain improvements.
• Conclusion:: HBOT as a downstream treatment candidate for the virtual-hypoxia / brain-metabolic phenotype, with durable long-term benefit in long COVID.
• Limitations:: Long-COVID population (not ME/CFS); open follow-up (no sham control); Efrati holds a financial stake in AVIV Scientific LTD.
• Certainty Assessment:: 0.55 raw × 0.85 long-COVID weight = discounted 0.47

11 Stadje et al. 2016 — Differential Diagnosis of Tiredness: Systematic Review

(Stadje et al. 2016)

Full Citation:: Stadje R, Dornieden K, Baum E, Becker A, Biroga T, Bösner S, Haasenritter J, Keunecke C, Viniol A, Donner-Banzhoff N. The differential diagnosis of tiredness: a systematic review. BMC Family Practice. 2016;17:147. DOI:: 10.1186/s12875-016-0545-5 PMID:: 27765009 Key Findings::

• Systematic review + meta-analysis of 26 primary-care studies of patients presenting with tiredness.
• Prevalence among those with tiredness: anaemia 2.8%; malignancy 0.6%; serious somatic disease 4.3%; depression 18.5%.
• Somatic-disease prevalence identical in controls without tiredness; depression more frequent among the tired. Conclusion:: Extensive investigation only warranted on specific history/exam findings. Low malignancy yield argues against blanket cancer screening in chronic fatigue absent red flags. Limitations:: Heterogeneity across studies; CFS not pooled; primary-care (not severe ME/CFS) population. Certainty Assessment:: 0.70 raw × 0.75 general population = discounted 0.53

12 Levine et al. 1992 — Does CFS Predispose to Non-Hodgkin’s Lymphoma?

(Levine et al. 1992)

Full Citation:: Levine PH, Peterson D, McNamee FL, O’Brien K, Gridley G, Hagerty M, Brady J, Fears T, Atherton M, Hoover R. Does chronic fatigue syndrome predispose to non-Hodgkin’s lymphoma? Cancer Research. 1992;52(19 Suppl):5516s-5518s. DOI:: (none on PubMed) PMID:: 1394166 Key Findings::

• Population-based cancer-incidence analysis (Nevada SEER-linked), NHL time trends before/after the 1984-86 CFS outbreaks.
• No statistically significant increase in NHL attributable to the CFS outbreak at state level; trends consistent with national SEER. Conclusion:: Negative: malignancy is not a common ME/CFS outcome; supports the differential being a red-flag search, not an automatic malignancy work-up. Limitations:: Ecological design, state-level (not individual), single region, 1992. Certainty Assessment:: 0.45 raw × 1.00 ME/CFS weight = discounted 0.45

13 Kobayashi et al. 2022 — Diagnoses Frequently Misattributed to Lyme Disease

(Kobayashi et al. 2022)

Full Citation:: Kobayashi T, Higgins Y, Melia MT, Auwaerter PG. Mistaken Identity: Many Diagnoses are Frequently Misattributed to Lyme Disease. The American Journal of Medicine. 2022;135(4):503-511. DOI:: 10.1016/j.amjmed.2021.10.040 PMID:: 34861197 Key Findings::

• Retrospective cohort, 1261 patients referred for possible Lyme; 1061 (84%) had no active Lyme.
• 690 (65%) received other diagnoses; 405 newly diagnosed. Leading: anxiety/depression 21%, fibromyalgia 11%, CFS 7%, migraine 7%.
• Non-syndromic newly diagnosed: MS n=11, malignancy n=8, Parkinson n=8, sarcoidosis n=4, ALS n=4. Conclusion:: Documents that serious organic disease (incl. malignancy, MS) can present as chronic multi-system symptoms and be missed — a red-flag search must not be foreclosed by a syndromic label. Limitations:: Referral-center selection, Lyme-specific framing, descriptive. Certainty Assessment:: 0.60 raw × 0.80 ME/CFS-adjacent weight = discounted 0.48

14 Kohn, Madden & Clarke 2011 — Refeeding in Anorexia Nervosa: Pathophysiology of Protein-Calorie Malnutrition

(Kohn, Madden, and Clarke 2011)

Full Citation:: Kohn MR, Madden S, Clarke SD. Refeeding in anorexia nervosa: increased safety and efficiency through understanding the pathophysiology of protein calorie malnutrition. Current Opinion in Pediatrics. 2011;23(4):390-394. DOI:: 10.1097/MOP.0b013e3283487591 PMID:: 21670680 Key Findings::

• “Start low and go slow” calorie prescription is unlikely to prevent refeeding syndrome and can prolong starvation.
• Carbohydrate proportion (>40% calories from CHO) is more important than total calories; continuous feeding with <40% CHO reduces refeeding risk.
• Postprandial hypoglycemia is a key risk. Conclusion:: Carbohydrate-driven refeeding physiology is general; applies to any starved/bedbound patient, including severe ME/CFS. Limitations:: Narrative review, paediatric/AN focus, no RCT. Certainty Assessment:: 0.60 raw × 0.80 anorexia-restricted-intake weight = discounted 0.48

15 Proulx-Cabana et al. 2022 — Initial Inpatient Management of Severe Anorexia Nervosa

(Proulx-Cabana et al. 2022)

Full Citation:: Proulx-Cabana S, Metras ME, Taddeo D, Jamoulle O, Frappier JY, Stheneur C. To Improve the Initial Inpatient Management of Adolescents Admitted with Severe Anorexia Nervosa: A Narrative Review and a Convenient Protocol. Nutrients. 2022;14(1):229. DOI:: 10.3390/nu14010229 PMID:: 35011105 Key Findings::

• Higher initial caloric intake supported; continuous NG feeding for BMI below 12.
• 72-h hypoglycemia monitoring; consider continuous cardiac monitoring (bradycardia under 30 beats per minute) and systematic phosphate supplementation. Conclusion:: Transferable monitoring of phosphate/hypoglycemia/bradycardia during refeeding of a severely malnourished bedbound patient. Limitations:: AN-specific, adolescent, protocol not validated in a trial. Certainty Assessment:: 0.55 raw × 0.80 severe-restricted-intake weight = discounted 0.44

16 Ridout et al. 2016 — Daily Laboratory Monitoring is of Poor Value in Eating Disorders

(Ridout et al. 2016)

Full Citation:: Ridout KK, Kole J, Fitzgerald KL, Ridout SJ, Donaldson AA, Alverson B. Daily Laboratory Monitoring is of Poor Health Care Value in Adolescents Acutely Hospitalized for Eating Disorders. Journal of Adolescent Health. 2016;59(1):104-109. DOI:: 10.1016/j.jadohealth.2016.03.015 PMID:: 27338666 Key Findings::

• NULL/negative: retrospective chart review, 196 admissions for eating disorders; guideline-recommended daily lab monitoring.
• Zero cases of refeeding syndrome; 3960 labs, 1.9% below normal, 0.05% critical; 0.28% prompted supplementation, none changed management.
• Cost $269,250 with value 1.04e-8 outcomes per dollar. Conclusion:: Directly challenges aggressive daily-lab-monitoring dogma in refeeding; supports risk-stratified (not routine-daily) monitoring in severe ME/CFS where lab access is difficult. Limitations:: Single center, retrospective, low baseline risk (mostly non-severe AN). Certainty Assessment:: 0.55 raw × 0.80 anorexia-restricted-intake weight = discounted 0.44

17 Araujo Castro & Vázquez Martínez 2018 — The Refeeding Syndrome: Importance of Phosphorus

(Araujo Castro and Vázquez Martínez 2018)

Full Citation:: Araujo Castro M, Vázquez Martínez C. The refeeding syndrome. Importance of phosphorus. Medicina Clínica. 2018;150(12):472-478. DOI:: 10.1016/j.medcli.2017.12.008 PMID:: 29448987 Key Findings::

• Hallmark hypophosphatemia, plus hypokalemia, hypomagnesemia, thiamine deficiency, sodium/fluid imbalance.
• Refeeding syndrome is potentially fatal but preventable; NICE 2006 guideline is the only treatment framework but based on low-quality evidence. Conclusion:: Establishes refeeding as a real, fatal-but-preventable risk in any malnourished patient started on feeding. Limitations:: Review, NICE guidance cited as low-evidence. Certainty Assessment:: 0.55 raw × 0.80 malnourished/restricted-intake weight = discounted 0.44

18 Kwiatkowska et al. 2025 — Comprehensive Care of the Patient with Refeeding Syndrome

(Kwiatkowska et al. 2025)

Full Citation:: Kwiatkowska M, Krupnik D, Wesołek F, Jonczyk A, Krzych Ł. Comprehensive care of the patient with Refeeding Syndrome. Polski Przegląd Chirurgiczny. 2025;97(5):64-71. DOI:: 10.5604/01.3001.0055.1957 PMID:: 41171118 Key Findings::

• Refeeding syndrome arises from overly aggressive/inadequate adaptive feeding, exacerbated by malnutrition.
• Causes respiratory failure, neurological disorders, circulatory failure, seizures; risk factors mostly modifiable.
• Guidance: gradual energy increase + regular monitoring of phosphorus, potassium, magnesium. Conclusion:: Documents systemic (including neuro/cardiac/seizure) consequences of refeeding syndrome; transferable electrolyte-monitoring during refeeding. Limitations:: Perioperative/surgical framing; review not systematic. Certainty Assessment:: 0.50 raw × 0.75 general critically-ill/malnourished weight = discounted 0.38

19 Norrington et al. 2012 — Medical Management of Acute Severe Anorexia Nervosa

(Norrington et al. 2012)

Full Citation:: Norrington A, Stanley R, Tremlett M, Birrell G. Medical management of acute severe anorexia nervosa. Archives of Disease in Childhood: Education and Practice Edition. 2012;97(2):48-54. DOI:: 10.1136/adc.2010.199885 PMID:: 21764823 Key Findings::

• Review of medical management of acute severe AN, system-based complication approach, feeding + refeeding-syndrome guidance.
• Identifies at-risk patients; system-based approach to complications. Conclusion:: Risk identification and feeding approach transferable to the severely malnourished bedbound patient. Limitations:: Paediatric, not validated. Certainty Assessment:: 0.50 raw × 0.80 acute-severe-restricted-intake weight = discounted 0.40

20 Hull et al. 2010 — EXCLAIM: Extended VTE Prophylaxis in Acutely Ill Medical Patients

(Hull et al. 2010)

Full Citation:: Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P, Vicaut E, Turpie AGG, Yusen RD. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Annals of Internal Medicine. 2010;153(1):8-18. DOI:: 10.7326/0003-4819-153-1-201007060-00004 PMID:: 20621900 Key Findings::

• Randomized, placebo-controlled trial, n=5963; acutely ill medical patients ≥40 y with reduced mobility (bed rest ± bathroom privileges).
• Extended enoxaparin reduced VTE 2.5% vs 4.0% (ARD -1.53%); increased major bleeding 0.8% vs 0.3%.
• Benefit concentrated in women, >75 y, and level-1 immobility; eligibility amended mid-trial. Conclusion:: Establishes that even short immobilization carries measurable VTE risk and that prophylaxis is a benefit/bleed trade-off — directly relevant to immobile severe ME/CFS. Limitations:: Immobility was acute/recent, not chronic; trial amended; bleeding risk in real bedbound ME/CFS (often anticoagulation-sensitive) is a safety concern. Certainty Assessment:: 0.70 raw × 0.75 general acutely-ill immobile weight = discounted 0.53

21 Clinebell et al. 2014 — Preventing Common Medical Complications of Catatonia

(Clinebell et al. 2014)

Full Citation:: Clinebell K, Azzam PN, Gopalan P, Haskett R. Guidelines for preventing common medical complications of catatonia: case report and literature review. Journal of Clinical Psychiatry. 2014;75(6):644-651. DOI:: 10.4088/JCP.13r08870 PMID:: 25004188 Key Findings::

• Case report + literature review of preventive guidelines for 4 immobility complications in catatonia (a severe immobile inpatient state).
• DVT/PE prophylaxis with anticoagulants for low-acute-bleeding-risk patients; pressure-ulcer prevention via frequent skin evaluation, support surfaces, repositioning; early enteral nutrition for prolonged immobility.
• Contracture data extrapolated from neurologic-injury studies. Conclusion:: A framework for pressure-ulcer (→ infection/sepsis) and aspiration-risk prevention in any prolonged-immobility patient; DVT prophylaxis as a benefit/bleed trade-off. Limitations:: Catatonia-specific, review not systematic, single case. Certainty Assessment:: 0.55 raw × 0.75 general immobile/institutionalized weight = discounted 0.41

22 Vigen, Thommessen & Rønning 2018 — Stroke Risk Is Low after Urgently Treated TIA

(Vigen, Thommessen, and Rønning 2018)

Full Citation:: Vigen T, Thommessen B, Rønning OM. Stroke Risk Is Low after Urgently Treated Transient Ischemic Attack. Journal of Stroke and Cerebrovascular Diseases. 2018;27(2):291-295. DOI:: 10.1016/j.jstrokecerebrovasdis.2017.08.037 PMID:: 29108805 Key Findings::

• Retrospective, n=261 TIA patients, urgent Stroke-Unit assessment + immediate prevention; follow-up to 2 y.
• Stroke incidence 1.5% at 1 month, 3.4% at 1 year, 4.2% at end of follow-up; median 90 d to recurrence.
• ABCD2 score poorly predictive. Conclusion:: New focal symptoms must be treated as possible TIA/stroke with urgent assessment — urgent referral is the safety-netting message, not benign attribution to ME/CFS. Limitations:: Single center, no control. Certainty Assessment:: 0.55 raw × 0.75 general TIA/stroke weight = discounted 0.41

23 El Husseini & Goldstein 2013 — “Code Stroke”: Hospitalized vs Emergency Department Patients

(El Husseini and Goldstein 2013)

Full Citation:: El Husseini N, Goldstein LB. “Code stroke”: hospitalized versus emergency department patients. Journal of Stroke and Cerebrovascular Diseases. 2013;22(4):345-348. DOI:: 10.1016/j.jstrokecerebrovasdis.2011.09.012 PMID:: 22206693 Key Findings::

• Retrospective, 93 in-hospital + 204 ED code-stroke activations, 1 y.
• Hospitalized patients less likely to have stroke/TIA (26.8% vs 51.4%) and less often thrombolyzed; 63.4% of in-hospital code strokes were mimics.
• “Altered mental status” was the sole symptom in 48% of in-hospital vs 10% of ED patients and independently predicted stroke mimic (OR 63.5). Conclusion:: In an already-ill/hospitalized (or bedbound, symptom-heavy) population, acute focal neurologic deficits are more likely true stroke than in the ED — a bedbound ME/CFS patient with sudden focal symptoms should NOT be presumed to have a “mimic”; the default must be urgent stroke work-up. Limitations:: Single center, retrospective. Certainty Assessment:: 0.55 raw × 0.75 general stroke weight = discounted 0.41

24 Uehara & Minematsu 2014 — Guidelines for Management of Patients with TIA

(Uehara and Minematsu 2014)

Full Citation:: Uehara T, Minematsu K. Guidelines for management of patients with transient ischemic attack. Frontiers of Neurology and Neuroscience. 2014;33:103-114. DOI:: 10.1159/000351911 PMID:: 24157559 Key Findings::

• Review of evidence-based TIA management guidelines.
• TIA is a medical emergency with high early-stroke risk; guidelines mandate urgent referral/expert evaluation/immediate treatment.
• TIA and minor ischemic stroke share pathophysiologic and preventive approaches. Conclusion:: TIA = emergency; sudden focal neurologic symptoms require urgent care regardless of background diagnosis. Limitations:: Review; guideline currency. Certainty Assessment:: 0.55 raw × 0.75 general TIA weight = discounted 0.41

25 Timbol & Baraniuk 2019 — Chronic Fatigue Syndrome in the Emergency Department

(Timbol and Baraniuk 2019)

Full Citation:: Timbol CR, Baraniuk JN. Chronic fatigue syndrome in the emergency department. Open Access Emergency Medicine. 2019;11:15-28. DOI:: 10.2147/OAEM.S176843 PMID:: 30666170 Key Findings::

• Anonymous online survey, n=282 physician-diagnosed CFS; scored core CFS symptoms, ED reasons, attitudes; open-text thematic analysis.
• 59% had gone to an ED; 1/3 of ED presentations consistent with orthostatic intolerance.
• 42% dismissed as psychosomatic; ED staff not knowledgeable about CFS; encounter favorability 3.6/10; non-attendees avoided ED. Conclusion:: The most frequent acute ED driver in CFS is orthostatic intolerance; a large fraction are dismissed as psychosomatic — safety-netting must arm patients/caregivers to communicate medical-emergency triggers credibly. Limitations:: Self-report, selection/social-desirability bias, n=282, US. Certainty Assessment:: 0.45 raw × 1.00 ME/CFS weight = discounted 0.45

26 Bowden et al. 2026 — ME/CFS Health, Labour Market, and Social Outcomes in New Zealand

(Bowden et al. 2026)

Full Citation:: Bowden N, McLeod K, Anns F, Catchpole L, Charlton F, Taylor B, Vallings R, Vu H, Tate W. Health, labour market, and social service outcomes for people with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome on a health or disability related benefit: an Aotearoa | New Zealand nationwide cross-sectional study using the integrated data infrastructure. BMC Public Health. 2026;26(1):1834. DOI:: 10.1186/s12889-026-27499-7 PMID:: 42032509 Key Findings::

• Nationwide IDI registry cohort, n=1902 working-age ME/CFS on health/disability benefit, propensity-score-matched comparisons.
• ME/CFS had significantly higher ED visits (18.8% vs 12.8%) and polypharmacy (>10 meds 32.8% vs 14.2%) vs general population.
• Lower hospitalization (11.2% vs 20.9%) than other benefit recipients; low employment (18.3%). Conclusion:: Elevated ED utilization in ME/CFS confirms the ED is a real contact point where safety-netting knowledge matters. Limitations:: Benefit-recipient subset only (not all ME/CFS), NZ-specific, cross-sectional, diagnostic-coding dependent. Certainty Assessment:: 0.60 raw × 1.00 ME/CFS weight = discounted 0.60

27 Klein et al. 2023 — Distinguishing Features of Long COVID Identified Through Immune Profiling

(Klein et al. 2023)

Full Citation:: Klein J, Wood J, Jaycox JR, Dhodapkar RM, Lu P, Gehlhausen JR, Tabachnikova A, et al. Distinguishing features of long COVID identified through immune profiling. Nature. 2023;623(7985):139-148. DOI:: 10.1038/s41586-023-06651-y PMID:: 37748514 Key Findings::

• Cross-sectional multidimensional immune phenotyping, n=275 (long COVID vs matched controls), Yale LISTEN + Mount Sinai PASC cohorts; machine learning separates long COVID from controls.
• Long COVID associated with reduced naive CD4+/CD8+ T cells, exhausted T cells (PD-1, TIM-3), exhausted B cells, elevated nonclassical monocytes.
• Exaggerated humoral responses against SARS-CoV-2 AND against latent viruses, notably EBV and VZV (higher antibody titres); lower morning cortisol. Conclusion:: Provides the canonical long-COVID immune-profiling signature (T-cell exhaustion + EBV/VZV antibody over-reactivity + hypocortisolism) that is convergent with ME/CFS immunopathology. Limitations:: Cross-sectional (no causality); self-report symptom grouping; long COVID only, no ME/CFS arm. Certainty Assessment:: 0.85 raw × 0.85 long-COVID weight = discounted 0.72

28 Phetsouphanh et al. 2024 — Improvement of Immune Dysregulation in Long COVID at 24 Months

(Phetsouphanh et al. 2024)

Full Citation:: Phetsouphanh C, et al. Improvement of immune dysregulation in individuals with long COVID at 24-months following SARS-CoV-2 infection. Nature Communications. 2024. DOI:: 10.1038/s41467-024-47720-8 PMID:: 38632311 Key Findings::

• Longitudinal 24-month follow-up of the Australian ADAPT cohort (mild-moderate long COVID vs recovered controls).
• Early immune-activation features — elevated PD-1/TIM-3 on CD4+/CD8+ T cells, elevated nucleocapsid IgG and neutralizing capacity at 3-8 months — resolved by 24 months.
• scRNA-seq at 24 months showed reconstituted naive T/B subsets, no residual exhaustion-score difference; 62% reported QoL improvement. Conclusion:: Long-COVID immune dysregulation is partly reversible and time-limited, contrasting with the durable exhaustion of ME/CFS. Limitations:: Mild-moderate cohort only; single site; longitudinal extension of the same ADAPT biobank as the 2022 report (not independent replication). Certainty Assessment:: 0.70 raw × 0.85 long-COVID weight = discounted 0.60

29 Petrov et al. 2025 — Comparable Immune Alterations in ME/CFS and Long COVID

(Petrov et al. 2025)

Full Citation:: Petrov S, Bozhkova M, Ivanovska M, Kalfova T, Dudova D, Nikolova R, Vaseva K, et al. Comparable immune alterations and inflammatory signatures in ME/CFS and Long COVID. Biomedicines. 2025;13(12):3001. DOI:: 10.3390/biomedicines13123001 PMID:: 41463013 Key Findings::

• Cross-sectional n=190 (65 CFS, 54 long COVID, 70 controls; Plovdiv, Bulgaria); lymphocyte subsets + cytokine profiling.
• Both conditions vs controls: lower lymphocytes, CD8+ T cells, NK cells; higher IL-6, TNF, IL-4, IL-10.
• No significant biomarker differences between ME/CFS and long COVID groups — comparable immune/inflammatory profiles. Conclusion:: Direct head-to-head evidence for immune convergence between ME/CFS and long COVID on lymphopenic/cytokine readouts. Limitations:: Single center; Fukuda criteria; limited cytokine panel; shares Plovdiv cohort with Petrov 2026 (same research group, not independent). Certainty Assessment:: 0.60 raw × 1.00 ME/CFS weight = discounted 0.60

30 Ivanovska et al. 2025 — Differential Characteristics: Long COVID vs ME/CFS

(Ivanovska et al. 2025)

Full Citation:: Ivanovska M, Murdjeva M. Differential Characteristics and Comparison Between Long-COVID Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Biomedicines. 2025. DOI:: 10.3390/biomedicines13112797 PMID:: 41301889 Key Findings::

• Narrative review comparing clinical presentation, pathophysiology, treatment of long COVID vs ME/CFS.
• Both involve viral persistence, immune dysregulation, endothelial dysfunction, autoimmunity (relative contributions uncertain); immune dysfunction flagged as a shared mechanism. Conclusion:: Confirms immune dysfunction as a shared thread between long COVID and ME/CFS; framing support. Limitations:: Non-systematic review; repeats contested CBT/GET claims without full critical appraisal. Certainty Assessment:: 0.45 raw × 1.00 ME/CFS weight = discounted 0.45

31 Hoeggerl et al. 2023 — EBV Reactivation Is Not Causative for Post-COVID-19 Syndrome (NULL)

(Hoeggerl et al. 2023)

Full Citation:: Hoeggerl AD, et al. Epstein-Barr virus reactivation is not causative for post-COVID-19-syndrome in individuals with asymptomatic or mild SARS-CoV-2 disease course. BMC Infectious Diseases. 2023. DOI:: 10.1186/s12879-023-08820-w PMID:: 37968601 Key Findings::

• Prospective cohort of SARS-CoV-2 seropositive blood donors with asymptomatic/mild COVID (Salzburg, Austria).
• Determined post-COVID syndrome rate; EBV was NOT reactivated in individuals reporting PCS in this mild-disease population (neopterin + EBV markers). Conclusion:: EBV reactivation may be a severity/dysregulation marker rather than causal — tempers a causal EBV-reactivation model of post-viral illness. Limitations:: Mild-disease donor population; may miss severe long COVID where reactivation is more prominent. Certainty Assessment:: 0.55 raw × 0.85 long-COVID weight = discounted 0.47

32 Lorenz et al. 2026 — Enhanced Antibody Reactivity to Specific EBV EBNA1 Epitopes in Post-COVID Syndrome

(Lorenz et al. 2026)

Full Citation:: Lorenz, et al. Patients Suffering From Post-COVID-19 Syndrome Feature Enhanced Antibody Reactivity Towards Specific Linear Epitopes Within EBV EBNA1. Scandinavian Journal of Immunology. 2026. DOI:: 10.1111/sji.70088 PMID:: 41518079 Key Findings::

• Retrospective cross-sectional n=96 (48 PCS vs 48 convalescents; Rostock, Germany); peptide microarray + ELISA for EBV EBNA1 IgG; autoantibody screen.
• Overall EBNA1 IgG binding similar, but PCS showed stronger reactivity to specific epitopes (glycine-alanine repeat residues 90-325; central 405-419, distinct from the MS epitope); no autoantibody increase. Conclusion:: Refines the EBV signal in post-infectious illness to epitope-specific enhanced reactivity, not general reactivation or autoimmunity. Limitations:: n=96, retrospective, exploratory. Certainty Assessment:: 0.50 raw × 0.85 long-COVID weight = discounted 0.43

33 Fleischer et al. 2024 — Cytokines and Cortisol May Not Be Reliable PASC Biomarkers (NULL)

(Fleischer et al. 2024)

Full Citation:: Fleischer, et al. Cytokines (IL-1beta, IL-6, TNF-alpha) and serum cortisol levels may not constitute reliable biomarkers to identify individuals with post-acute sequelae of COVID-19. Therapeutic Advances in Neurological Disorders. 2024. DOI:: 10.1177/17562864241229567 PMID:: 38348267 Key Findings::

• Prospective cohort n=178 (91 ongoing PASC, 40 resolved, 34 infected no PASC, 13 never infected; Essen, Germany); serum IL-1beta, IL-6, TNFalpha + cortisol.
• No cytokine/cortisol differences between groups. Conclusion:: Single-timepoint peripheral cytokines/cortisol are unreliable PASC biomarkers — conflicts with Klein 2023’s lower-cortisol finding; a caution for ME/CFS biomarker claims. Limitations:: Single timepoint; the study’s own “non-organic genesis” conclusion is not warranted by a null biomarker result. Certainty Assessment:: 0.55 raw × 0.85 long-COVID weight = discounted 0.47

34 Kaplan 2026 — Therapeutic Plasma Exchange and Immunomodulatory Strategies in Post-Infectious Syndromes

(Kaplan 2026)

Full Citation:: Kaplan. Therapeutic plasma exchange and immunomodulatory strategies in post-infectious syndromes: A review of immune dysregulation in PTLDS, long COVID, ME/CFS, and PANS/PANDAS. Transfusion and Apheresis Science. 2026. DOI:: 10.1016/j.transci.2026.104482 PMID:: 42391726 Key Findings::

• Narrative review of immune dysregulation across PTLDS, long COVID, ME/CFS, PANS/PANDAS; evaluates IVIG, rituximab, TPE.
• Immune-targeted treatment evidence strongest in biomarker-defined subsets; phase III RituxME (ME/CFS) and phase II TPE (post-COVID) FAILED in unselected populations. Conclusion:: Reinforces that blanket immunotherapy lacks support without immune-subset stratification; a caution against borrowing oncology checkpoint/CAR-T approaches without selection biomarkers. Limitations:: Non-systematic; single-author; integrative-medicine affiliation. Certainty Assessment:: 0.50 raw × 0.85 mixed post-infectious weight = discounted 0.43

35 Souma et al. 2026 — Irisin Signaling Resistance in ME: TSP-1–HSP90α–αvβ5 Axis for PEM

(Souma et al. 2026)

Full Citation:: Souma B, Elremaly W, Akoume MY, Elbakry M, Godbout C, Moreau A. Irisin Signaling Resistance in Myalgic Encephalomyelitis: A Proposed Mechanistic Framework for Post-Exertional Malaise Involving the TSP-1–HSP90α–αvβ5 Axis. International Journal of Molecular Sciences. 2026;27(11):4770. DOI:: 10.3390/ijms27114770 PMID:: 42278300 Key Findings::

• Cross-sectional n=92 ME/CFS (CCC) vs 44 sedentary controls (Moreau group, CHU Sainte-Justine / ICanCME / OMF Collaborative Center); plasma irisin + TSP-1 at baseline and after a 90-min standardized mechanical stress challenge.
• ME patients had lower baseline irisin (\(p < 0.05\)) and a blunted exertional irisin response (\(p < 0.05\)).
• Paradox: baseline irisin independently predicted fatigue severity (MFI-20, β=0.728, \(p = 0.018\)); moderate-to-severe patients showed elevated irisin AND TSP-1 (\(p < 0.05\)).
• Functional CDS (Jurkat cells): TSP-1 inhibits irisin signaling concentration-dependently; irisin signaling requires αvβ5 integrin + extracellular HSP90α; TSP-1 is the dominant antagonist. Conclusion:: Proposes a TSP-1–HSP90α–αvβ5 axis where circulating TSP-1 antagonizes irisin signaling, producing “irisin signaling resistance” that contributes to the metabolic dysfunction underlying PEM. Limitations:: Single cohort; cross-sectional; mechanical stress challenge (not full exercise); Jurkat immune-cell model (not myocyte); irisin ELISA specificity caveat (see Elsen 2014); shares Moreau-group biobank with Nepotchatykh 2020/2023 and ChalderMoreau 2026 (not independent). Certainty Assessment:: 0.55 raw × 1.00 ME/CFS weight = discounted 0.55

36 Boström et al. 2012 — PGC1-α-Dependent Myokine Irisin Drives Browning of White Fat (FOUNDATIONAL)

(Boström et al. 2012)

Full Citation:: Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-468. DOI:: 10.1038/nature10777 PMID:: 22237023 Key Findings::

• Foundational discovery of irisin: muscle FNDC5 cleaved to irisin, released with exercise/PGC1-α; drives browning of white adipose and thermogenesis. Conclusion:: The naming/discovery source for the irisin myokine field — establishes irisin as an exercise-induced metabolic signal. Limitations:: Human-relevance caveats emerged later (see Elsen 2014); largely mouse + cultured myocyte data. Certainty Assessment:: 0.85 raw × 0.75 general-population weight = discounted 0.64

37 Kim et al. 2018 — Irisin Acts via αV Integrin Receptors (FOUNDATIONAL)

(Kim et al. 2018)

Full Citation:: Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, et al. Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Cell. 2018;175(7):1756-1768.e17. DOI:: 10.1016/j.cell.2018.10.025 PMID:: 30550785 Key Findings::

• Identifies αV integrins (αvβ5 dominant) as the irisin receptor in osteocytes and adipocytes. Conclusion:: Establishes the receptor mechanism Souma 2026 invokes (TSP-1 antagonizing the αvβ5 axis). Limitations:: Mouse + cell culture; no ME/CFS data. Certainty Assessment:: 0.80 raw × 0.50 other-disease-model weight = discounted 0.40

38 A et al. 2023 — Irisin Two-Step Signaling Requires Extracellular Hsp90α (MECHANISTIC)

A et al. (2023)

Full Citation:: A M, Wales TE, Zhou H, Draga-Coletă SV, Gorgulla C, Blackmore KA, et al. Irisin acts through its integrin receptor in a two-step process involving extracellular Hsp90α. Molecular Cell. 2023;83(11):1903-1920.e12. DOI:: 10.1016/j.molcel.2023.05.008 PMID:: 37267907 Key Findings::

• Irisin signals via αvβ5 in a two-step process requiring extracellular Hsp90α (eHsp90α) secreted with exercise; cryo-EM + HDX docking model (2.98 Å). Conclusion:: Defines the HSP90α–αvβ5 machinery Souma 2026 reports TSP-1 antagonizes. Limitations:: In vitro; first author indexed as “A M” (surname A, given Mu). Certainty Assessment:: 0.80 raw × 0.40 in-vitro weight = discounted 0.32

39 Rogers et al. 2014 — TSP-1/CD47 Regulation of Vascular Responses (MECHANISTIC)

(Rogers et al. 2014)

Full Citation:: Rogers NM, Sharifi-Sanjani M, Csányi G, Pagano PJ, Isenberg JS. Thrombospondin-1 and CD47 regulation of cardiac, pulmonary and vascular responses in health and disease. Matrix Biology. 2014;37:92-101. DOI:: 10.1016/j.matbio.2014.01.002 PMID:: 24418252 Key Findings::

• TSP-1, via CD47, is a key endogenous inhibitor of NO signaling in the cardiovascular system; elevated in platelet/endothelial activation and disease. Conclusion:: Provides the NO-suppression mechanism Souma 2026 cites (TSP-1 impairs NO signaling). Limitations:: General vascular biology, not ME/CFS. Certainty Assessment:: 0.75 raw × 0.75 general-population weight = discounted 0.56

40 Roberts et al. 2017 — Matricellular Proteins Regulate Redox/NO Signaling (MECHANISTIC)

(Roberts, Kaur, and Isenberg 2017)

Full Citation:: Roberts DD, Kaur S, Isenberg JS. Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer. Antioxidants & Redox Signaling. 2017;27(12):874-911. DOI:: 10.1089/ars.2017.7140 PMID:: 28712304 Key Findings::

• TSP-1 and other matricellular proteins regulate redox and NO signaling across vascular, immune, and cancer biology. Conclusion:: Supports TSP-1 as a broad metabolic/redox antagonist that Souma 2026 extends to irisin signaling. Limitations:: General biology review. Certainty Assessment:: 0.75 raw × 0.75 general-population weight = discounted 0.56

41 Bazzazi et al. 2018 — TSP1 Inhibits VEGF-Akt-eNOS (COMPUTATIONAL)

(Bazzazi et al. 2018)

Full Citation:: Bazzazi H, Zhang Y, Jafarnejad M, Isenberg JS, Annex BH, Popel AS. Computer Simulation of TSP1 Inhibition of VEGF-Akt-eNOS: An Angiogenesis Triple Threat. Frontiers in Physiology. 2018;9:644. DOI:: 10.3389/fphys.2018.00644 PMID:: 29899706 Key Findings::

• Computational model: TSP-1 inhibits the VEGF-Akt-eNOS axis at multiple nodes, suppressing NO production and angiogenesis. Conclusion:: Mechanistic support for TSP-1 as a systemic NO antagonist, complementary to the irisin-TSP-1 antagonism in Souma 2026. Limitations:: In silico only. Certainty Assessment:: 0.50 raw × 0.30 in-silico weight = discounted 0.15

42 Ercan et al. 2026 — Serum Irisin Not Altered in Fibromyalgia (NULL)

(Ercan et al. 2026)

Full Citation:: Ercan Z, Esmez O, Danis EG, Dagdeviren B, Deniz G. Serum Isthmin-1 and Irisin profiles and their association with clinical parameters in fibromyalgia: a cross-sectional study. Rheumatology International. 2026;46(8):225. DOI:: 10.1007/s00296-026-06239-5 PMID:: 42550262 Key Findings::

• n=21 female FM (ACR 2016) vs 21 matched controls: serum irisin did NOT differ (\(p = 0.580\)); isthmin-1 was significantly reduced in FM and correlated with pain/depression. Conclusion:: NULL for irisin — contradicts a simple “low irisin = chronic fatigue/pain” model; irisin is not a robust cross-condition fatigue/pain biomarker. Limitations:: Small n; single center. Certainty Assessment:: 0.40 raw × 0.80 fibromyalgia weight = discounted 0.32

43 Belviranlı et al. 2026 — CoQ10 Restores Irisin Signaling in FM Model (PRECLINICAL)

(Belviranlĭ, Okudan, and Sezer 2026)

Full Citation:: Belviranlı M, Okudan N, Sezer T. Coenzyme Q10 improves redox homeostasis, mitochondrial biogenesis, and irisin signaling in fast- and slow-twitch muscle fibers in a reserpine-induced fibromyalgia-like myalgia model. Life Sciences. 2026;394:124366. DOI:: 10.1016/j.lfs.2026.124366 PMID:: 41921657 Key Findings::

• Reserpine-induced FM-like myalgia in female Wistar rats depletes muscle CoQ10, elevates oxidative damage, suppresses AMPK/SIRT1/PGC1-α/FNDC5 (irisin); CoQ10 restores irisin signaling + mitochondrial biogenesis. Conclusion:: Independent link between mitochondrial/redox status and the FNDC5-irisin axis — supports “blunted irisin = metabolic adaptation failure” framing. Limitations:: Preclinical (rat); no human dosing. Certainty Assessment:: 0.45 raw × 0.50 animal-model weight = discounted 0.23

44 dos Santos et al. 2023 — Whole-Body Vibration Raises Irisin in FM (RCT)

(Santos et al. 2023)

Full Citation:: dos Santos JM, Taiar R, Ribeiro VGC, da Silva Lage VK, Scheidt Figueiredo PH, Costa HS, et al. Whole-Body Vibration Training on Oxidative Stress Markers, Irisin Levels, and Body Composition in Women with Fibromyalgia: A Randomized Controlled Trial. Bioengineering. 2023;10(2):260. DOI:: 10.3390/bioengineering10020260 PMID:: 36829754 Key Findings::

• RCT n=40 women with FM: 6 weeks whole-body vibration training increased plasma irisin and reduced oxidative stress (TBARS) and visceral fat vs untrained controls. Conclusion:: A low-impact mechanical stimulus can RAISE irisin in a chronic-pain cohort — the therapeutic lever Souma 2026 proposes, via mechanical (not pharmacological) intervention. Limitations:: FM cohort (not ME/CFS); n=40; short follow-up. Certainty Assessment:: 0.55 raw × 0.80 fibromyalgia weight = discounted 0.44

45 Elsen et al. 2014 — Does Irisin Play a Role in Humans? (CONTROVERSY)

(Elsen, Raschke, and Eckel 2014)

Full Citation:: Elsen M, Raschke S, Eckel J. Browning of white fat: does irisin play a role in humans? Journal of Endocrinology. 2014;222(1):R25-R38. DOI:: 10.1530/JOE-14-0189 PMID:: 24781257 Key Findings::

• Exercise regulation of FNDC5 mRNA could not be reproduced in several human studies; the presence of irisin in humans is questionable and commercial ELISA kits give conflicting data. Conclusion:: Canonical caution against over-interpreting circulating irisin levels — directly relevant to Souma 2026’s plasma irisin ELISA measurements. Limitations:: Review; measurement controversy unresolved. Certainty Assessment:: 0.70 raw × 0.75 general-population weight = discounted 0.53

46 Cicek et al. 2023 — Irisin Lower in Depression, Tracks Energy (INDIRECT)

(Cicek, Tuygar Okutucu, and Ozturk 2023)

Full Citation:: Cicek MA, Tuygar Okutucu F, Ozturk N. Irisin, adropin, and preptin as biomarkers of energy dysregulation in depressive disorder. Current Medical Research and Opinion. 2023;39(9):1263-1270. DOI:: 10.1080/03007995.2023.2247317 PMID:: 37574912 Key Findings::

• n=117 depression vs 59 controls: irisin/adropin/preptin lower in depression, positively correlated with quality of life, negatively with depression severity/functional impairment. Conclusion:: Consistent with “low irisin = low energy” — supports the directionality Souma 2026 inverts in severe ME (paradoxically high irisin with worse fatigue). Limitations:: Depression population (fatigue, not ME/CFS); cross-sectional. Certainty Assessment:: 0.50 raw × 0.75 general-population weight = discounted 0.38

47 Lapauw et al. 2026 — Irisin Panel Poor Sarcopenia Diagnostic Accuracy (NULL)

(Lapauw et al. 2026)

Full Citation:: Lapauw L, Vermeiren L, Vercauteren L, Amini N, Peeters L, Dalle S, et al. An exploratory multi-biomarker panel including fecal calprotectin, Brain-Derived Neurotrophic Factor, Fibroblast-Growth Factor-21 and irisin shows poor diagnostic accuracy for detecting probable sarcopenia in community-dwelling older persons. Aging Clinical and Experimental Research. 2026;38(1):127. DOI:: 10.1007/s40520-026-03368-6 PMID:: 41940919 Key Findings::

• Multi-biomarker panel including irisin showed poor diagnostic accuracy for probable sarcopenia in community-dwelling older adults. Conclusion:: Circulating irisin alone is not a strong standalone biomarker — supports reading Souma 2026 as a signaling-resistance axis (with TSP-1), not a simple irisin blood test. Limitations:: Older-adult population; exploratory panel. Certainty Assessment:: 0.45 raw × 0.75 general-population weight = discounted 0.34

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